Regulatory T cell alterations in early pregnancy linked to spontaneous preterm labor

Regulatory T cell alterations in early pregnancy linked to spontaneous preterm labor | Image Credit: © weyo - © weyo - stock.adobe.com.

There is a link between alterations in specific regulatory T cell subpopulations in the early first trimester and idiopathic spontaneous preterm labor, according to a recent study published in the American Journal of Obstetrics & Gynecology.¹

Spontaneous preterm labor is the leading cause of neonatal morbidity and mortality, with data indicating multiple pathological processes impacting this event.² Experts have suggested the breakdown of the maternal-fetal tolerance as a factor behind spontaneous preterm labor.¹

Tregs are vital factors of maternal-fetal tolerance, with adequate Treg numbers and function reducing the risks of multiple pregnancy complications. This highlights clinical implications from dynamic immunological shifts during pregnancy.

“Advancements in the field of reproductive immunology hold significant promise for enhancing prenatal care and reducing the incidence of spontaneous preterm births,” said investigators. The study was conducted to evaluate the link between altered Tregs subpopulations and spontaneous preterm birth.

Pregnant patients with at least 2 prior spontaneous abortions recruited at 10 to 11 weeks’ gestation between January 2020 and January 2021 were included in the analysis. These patients underwent blood sample collection at routine prenatal care appointments.

Exclusion criteria included diabetes mellitus, autoimmune diseases, primary hypertension, and treatment with vaginal progesterone before blood sample collection. Analysis of peripheral blood was performed within 5 hours of collection.

Treg subpopulations were evaluated using the DURAClone IM Tregs kit (Beckman Coulter, Brea, California, USA), which performs surface and intracellular labeling with tubes containing dried monoclonal antibodies. Surface labeling included CD45RA-FITC, CD25-PE, CD39-PC5.5, CD4-PC7, CD3-APC A750, and CD45-KrO.

Forward and side scatter was used for lymphocytes gating, with Tregs gated as CD45+CD3+CD4+CD25+FoxP3+ Tregs. Gating was performed for the CD3+CD4+ population.

There were 43 participants included in the final analysis, 7 of whom experienced spontaneous preterm labor while 36 delivered at term and were considered controls. Patients were aged a mean 35 years at enrollment in the spontaneous labor group vs 34 years in the control group.

Urinary tract infections were reported in 1 participant from each group, and 2 controls presented with gestational hypertension and gestational diabetes. Vaginal delivery was reported in 37 patients and cesarean section in 6. Similar smoking rates were reported across groups. No cases of preterm premature rupture of membranes were identified.

The CD4+CD25+FoxP3+ population was identified as the primary focus of the analysis. In the preterm labor group, significantly reduced CD4+CD25+Foxp3+ expression was reported compared to the control group. Medians were 0.0410×10ˆ9/L vs 0.0550×10ˆ9/L, respectively.

Patients with preterm labor also reported a reduced CD4+CD25+FoxP3+CD45RA− population vs controls. According to investigators, “this particular subpopulation is critical for understanding the adaptive immune responses during pregnancy,” as the immunosuppressive functions of effector Tregs are key aspects of fetal-maternal tolerance.

Tregs Helios+ populations were also significantly reduced in the spontaneous preterm labor group vs the control group, with medians of 0.0270×10ˆ9/L vs 0.0370×10ˆ9/L, respectively. This indicated disruption in a vital regulatory landscape for pregnancy maintenance, as Helios has been linked to the suppressive abilities of Tregs.

Finally, the CD4+CD25+FoxP3+CD39− Tregs populations were reduced in patients delivering preterm. CD39 plays a key role in promoting an anti-inflammatory milieu, indicating its decreased presence in Tregs may contribute to the pathophysiology of spontaneous preterm labor.

These results indicated several reduced Treg subpopulations in patients with spontaneous preterm labor. Investigators concluded “in pregnancies resulting in idiopathic spontaneous preterm labor, early changes in selected lymphocyte subpopulations are already present at the end of the first trimester.”

References

1. Lastuvka Z, Koprivova H, et al. Reduced number of regulatory T cells in maternal circulation precede idiopathic spontaneous preterm labor in a subset of patients. Am J Obstet Gynecol. 2025;232:222.e1-11. doi:10.1016/j.ajog.2024.11.001
2. Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science. 2014;345(6198):760-5. doi:10.1126/science.1251816